Chiral Purification Method for Key Intermediate of GLP-1 Receptor Agonist

Abstract

Chiral purification method of key intermediate of GLP-1 receptor agonist. The present invention belongs to the field of organic chemical synthesis. To solve the problem that it is difficult to obtain a high-purity product of (S)-oxetan-2-ylmethanamine prepared by the current process route, the technical solution provided by the present invention is as follows: 1) The compound of formula V is salted with an acid to form the compound of formula VI; 2) The compound of formula VI is freed under alkaline conditions to obtain the compound of formula VIII. The beneficial effects of the present invention are: By using the purification method of synthesizing (S)-oxetan-2-ylmethanamine of the present invention, the product has good stability after being salted with D-tartaric acid / D-mandelic acid and is not easily decomposed and ring-opened. Then, free with a base to achieve the effect of chiral resolution, so that the ee value of the final product VIII reaches more than 98%. The operation is convenient, avoiding the use of high-risk solvents such as 36% concentrated hydrochloric acid, and improving the operability of the process.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemical synthesis, and particularly relates to a key intermediate of a GLP-1 receptor agonist Purification method Background Art

[0002] Compound A is a key intermediate for synthesizing GLP-1 receptor agonists, as shown below:

[0003]

[0004] In addition, Compound A is also a key intermediate for other GLP-1 receptor agonist analogs

[0005] Currently, the method for synthesizing Compound A in the relevant literature is mainly one scheme. Its synthetic route is as shown below. By debenzylating to form a hydrochloride salt and then freeing it to obtain the intermediate chiral amine VI. However, there are two problems that are likely to occur in this step of the reaction: (1) Using 36% concentrated hydrochloric acid to form a salt is likely to cause the opening of the oxygen-containing four-membered ring, and the reaction control is relatively complex, and it is impossible to obtain a good intermediate. (2) The ee value of the finally obtained chiral amine product VI is relatively low, and the ee value cannot reach more than 98%, and purification is required

[0006]

[0007] To sum up, as a key intermediate for synthesizing GLP-1 receptor agonist analogs, (S)-oxetan-2-ylmethanamine with high chiral purity is required as a raw material. However, the currently reported synthetic methods cannot meet the requirements of high chiral purity, and there is still much room for improvement Summary of the Invention

[0008] In order to improve the problem that it is difficult to obtain a high-purity product of (S)-oxetan-2-ylmethanamine prepared by the current process route, a new method for salifying and purifying (S)-oxetan-2-ylmethanamine is provided. Specifically, it includes the following reaction steps

[0009] 1) The compound of formula V forms a salt with an acid to form the compound of formula VI

[0010] 2) The compound of formula VI is freed under alkaline conditions to obtain the compound of formula VII

[0011] Its reaction route is as follows

[0012]

[0013] The specific technical solution is as follows

[0014] 1) Add the salifying reagent (1.5 eq) and ethanol (7 vol) into the reaction kettle. Then, under the protection of nitrogen, heat up to 60 - 75 °C, stir until it becomes clear, and keep the temperature to dropwise add the ethanol (3 vol) solution of compound V (1 eq). After the addition is completed, keep the temperature for reaction for 1 - 4 h;

[0015] 2) After the reaction is completed, cool down to 0 - 10 °C and keep the temperature for stirring for 3 h;

[0016] 3) Filter, wash the filter cake with ethanol (1 vol), and dry to obtain the compound of formula VI;

[0017] 4) Add the compound of formula VI (1 eq) and dichloromethane (5 vol) into the reaction kettle, cool down to 10 - 20 °C and stir;

[0018] 5) Control the temperature below 20 °C, dropwise add the aqueous solution (4 vol) of the base (2 eq). After the addition is completed, control the temperature at 10 - 20 °C and stir for 3 h;

[0019] 6) After the reaction is completed, let it stand for liquid separation, and extract the aqueous phase with dichloromethane (5 vol);

[0020] 7) Concentrate the organic phase to obtain the compound of formula VII.

[0021] Preferably, the salifying reagent required in step 1) can be selected from D-tartaric acid, D-mandelic acid, etc., and D-tartaric acid is preferred; through multiple experiments by the applicant, not all salifying reagents are applicable to the present invention. For example, acetic acid results in no salification, and hydrochloric acid causes the product to ring open.

[0022] Preferably, the base required in step 5) is sodium hydroxide, potassium hydroxide, etc., and sodium hydroxide is preferred.

[0023] The beneficial effects of the present invention are as follows:

[0024] Adopting the purification method for synthesizing (S)-oxetan-2-ylmethanamine of the present invention, after salifying with D-tartaric acid / D-mandelic acid, the product has good stability and is not easily decomposed and ring-opened. Then, using the base for liberation achieves the effect of chiral resolution, making the ee value of the final product VII reach more than 98%. The operation is convenient, avoiding the use of high-risk solvents such as 36% concentrated hydrochloric acid, and improving the operability of the process. Description of the Drawings

[0025] Figure 1 It is the normal phase spectrum of Example 1;

[0026] Figure 2 It is the GC spectrum of Example 1;

[0027] Figure 3 It is the H-NMR spectrum of Example 1;

[0028] Figure 4It is the normal-phase spectrum of Example 2;

[0029] Figure 5 It is the GC spectrum of Example 2;

[0030] Figure 6 It is the H-NMR spectrum of Example 2;

[0031] Figure 7 It is the H-NMR spectrum of Example 3. Detailed implementation manners

[0032] Example 1

[0033] (1) At 20 - 30 °C, the hydrogenated crude V (S)-oxetan-2-ylmethanamine (250 g) was mixed and dissolved clearly with ethanol (1.39 kg);

[0034] (2) D-Tartaric acid (646 g) and ethanol (595 g) were added to the reaction vessel, heated to 60 - 75 °C, stirred until dissolved clearly, and then the mixed solution prepared in (1) was added dropwise;

[0035] (3) React at 60 - 75 °C for 3 h. After the reaction, cool down to 0 - 10 °C and stir for 3 h while keeping warm, filter and wash, and dry at 50 °C to obtain 579 g of compound VI.

[0036] (4) Compound VI (579 g) and dichloromethane (3.84 kg) were added to the reaction vessel and stirred at 10 - 20 °C;

[0037] (5) The prepared sodium hydroxide (195 g) / water (2.31 kg) solution was added dropwise to the reaction vessel, and the temperature was controlled at 10 - 20 °C and stirred for 3 h;

[0038] (6) After the reaction was completed, liquid separation was carried out, extracted with dichloromethane, and the solvent was dried to obtain 127 g of (S)-oxetan-2-ylmethanamine with a yield of 60%.

[0039] Figures 1 - 3 They are the normal-phase spectrum, GC spectrum and H-NMR spectrum respectively. It can be seen from the figure that the GC purity is 98.94%, the normal-phase ee value is 98.28%, and the NMR is correct.

[0040] Example 2

[0041] (1) At 20 - 30 °C, the hydrogenated crude V (S)-oxetan-2-ylmethanamine (275 g) was mixed and dissolved clearly with ethanol (1.52 kg);

[0042] (2) D-Mandelic acid (720.4 g) and ethanol (653 g) were added to the reaction vessel, heated to 60 - 75 °C, stirred until dissolved clearly, and then the mixed solution prepared in (1) was added dropwise;

[0043] (3) React at 60 - 75 °C for 3 h. After the reaction is completed, cool down to 0 - 10 °C, keep warm and stir for 3 h, filter and wash, and dry at 50 °C to obtain 635 g of Compound VII.

[0044] (4) Add Compound F (635 g) and dichloromethane (4.21 kg) to the reaction vessel and stir at 10 - 20 °C;

[0045] (5) Drop the prepared sodium hydroxide (214 g) / water (2.54 kg) solution into the reaction vessel and stir at a controlled temperature of 10 - 20 °C for 3 h;

[0046] (6) After the reaction is completed, separate the liquid, extract with dichloromethane, and drain the solvent to obtain 140 g of (S)-oxetan-2-ylmethanamine with a yield of 55%.

[0047] Figures 4 - 6 They are the normal-phase spectrum, GC spectrum, and H-NMR spectrum respectively. It can be seen from the figures that the GC purity is 98.89%, the normal-phase ee value is 99.02%, and the NMR is correct.

[0048] Example 3

[0049] (1) At 20 - 30 °C, mix the hydrogenated crude product of V, (S)-oxetan-2-ylmethanamine (200 g) with ethanol (1.12 kg) to make a clear solution;

[0050] (2) Drop 36% hydrochloric acid (349 g) into the reaction solution;

[0051] (3) React at 60 - 75 °C for 3 h. After the reaction is completed, cool down to 0 - 10 °C, keep warm and stir for 3 h, filter and wash, and dry at 50 °C to obtain 300 g of crude product, but the structure does not match.

[0052] Figure 7 It is a nuclear magnetic resonance spectrum. Judged by nuclear magnetic resonance detection, it is a ring-opening compound

[0053] Example 4

[0054] (1) At 20 - 30 °C, mix the hydrogenated crude product of V, (S)-oxetan-2-ylmethanamine (200 g) with ethanol (1.12 kg) to make a clear solution;

[0055] (2) Drop acetic acid (206 g) into the reaction solution;

[0056] (3) React at 60 - 75 °C for 3 h. Monitor the reaction by TLC. The reaction raw materials have not reacted and no new substances have appeared:

[0057] Salt-forming reagent Final product yield Remarks Acetic acid N / A Not salt-formed Hydrochloric acid N / A The product ring-opens, not applicable .

Claims

1. A chiral purification method for a key intermediate of a GLP-1 receptor agonist, characterized in that, The purification method described above comprises the following steps: 1) Add a salifying reagent and ethanol into a reaction kettle, then heat up to 60 - 75 °C under nitrogen protection, stir until clear, keep warm and dropwise add an ethanol solution of crude compound V. After the dropping is completed, carry out a reaction while keeping warm; the salifying reagent is D-tartaric acid and / or D-mandelic acid; wherein Compound V is ; 2) After the reaction is completed, cool down to 0 - 10 °C and stir while keeping warm; 3) Filter, wash the filter cake with a small amount of ethanol, and dry to obtain the compound; 4) Add the compound obtained in step 3) and dichloromethane into the reaction kettle, cool down to 10 - 20 °C and stir; 5) Control the temperature below 20 °C, dropwise add an alkali solution. After the dropping is completed, control the temperature at 10 - 20 °C and stir; 6) After the reaction is completed, let it stand for liquid separation, and extract the aqueous phase with dichloromethane; 7) Concentrate the organic phase to obtain (S)-oxetan-2-ylmethanamine.

2. The chiral purification method of the key intermediate of the GLP-1 receptor agonist according to claim 1, characterized in that, The alkali is sodium hydroxide and / or potassium hydroxide.

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